3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof

ABSTRACT

THE PRESENT INVENTION PROVIDES NEW AMINOPROPANOL DERIVATIVES OF THE FORMULA:   (3,4-DI(HO-)PHENYL)-CH(-CH2-OH)-CH2-NH-R1   WHEREIN R1 IS HYDROGEN, CYCLOALKYL OF 3 TO 7 CARBON ATOMS, ALKYL OF 1 TO 8 CARBON ATOMS, CYCLOALKYLALKYL, IN WHICH THE CYCLOALKYL RING IS OF 3 TO 7 CARBON ATOMS AND THE ALKYL RESIDUE IS OF 1 TO 6 CARBON ATOMS, OR PHENYLALKYL OR DIPHENYLALKYL, IN WHICH THE PHENYL RADICALS MAY BE SUBSTITUTED IN THE 3, 4 OR 5 POSITION BY 1 TO 3 HYDROXY OR METHOXY GROUPS, OR IN THE 3,4 POSITION BY A METHYLENEDIOXY GROUP, AND IN WHICH THE ALKYL RESIDUE IS OF 1 TO 6 CARBON ATOMS, AND ACID ADDITION SALTS THEREOF. PROCESSESS FOR THE PRODUCTION THEREOF AND INTERMEDIATES THEREFOR ARE ALSO DESCRIBED. THE COMPOUNDS EXHIBIT BRONCHOLYTIC PROPERTIES.

United States Patent US. Cl. 260-5706 13 Claims ABSTRACT OF THEDISCLOSURE The present invention provides new aminopropanol denvativesof the formula:

(I) H: O H H0- CH-CHr-NH-Rt wherein and acid addition salts thereof.

Processes for the production thereof and intermediates therefor are alsodescribed.

The compounds exhibit broncholytic properties.

The present invention relates to aminopropanol derivatives.

In accordance with the invention there are provided new compounds ofFormula I,

l CHzOH HO CH-CHr-NH-Rt wherein R is hydrogen, cycloalkyl of 3 to 7carbon atoms, alkyl of 1 to '8 carbon atoms, cycloalkylalkyl, in whichthe cycloalkyl ring is of 3 to 7 carbon atoms and the alkyl residue isof 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, in which thephenyl radicals may be substituted in the 3, 4 or 5 position by 1 to 3hydroxy or methoxy groups, or in the 3,4 position by a methylenedioxygroup, and in which the alkyl residue is of 1 to 6 carbon atoms, a

and acid addition salts thereof.

Further, in accordance with the invention a compound of Formula I may beobtained by a process comprising (2.) Converting the ether groups intohydroxy groups in a compound of Formula II,

(iJHaOH R20 CH-C Hg-NH-Rl wherein R is as defined above, and

R, is methyl, ethyl or benzyl,

3,804,899 Patented Apr. 16, 1974 to produce a compound of Formula Ia,

([lHzOH H0- -cH-cm-NHRi (Ia) wherein (b) Hydrogenolyticallydebenzylating a compound of Formula III,

(EHIOH Bro CH-CHPliI-Rl R3 (III) wherein R is hydrogen, cycloalkyl of 3to 7 carbon atoms, alkyl of 1 to 8 carbon atoms, cycloalkylalkyl, inwhich the cycloalkyl ring is of 3 to 7 carbon atoms and the alkylresidue is of 1 to 6 carbon atoms, or phenylalkyl or diphenylalkyl, inwhich the phenyl radicals may be substituted in the 3, 4 or 5 postion by1 to 3 hydroxy or methoxy groups, or in the 3,4 position by amethylenedioxy group, and are separated from the nitrogen atom by atleast two carbon atoms, and in which the alkyl residue is of 2 to 6carbon atoms,

R is hydrogen or benzyl, and

R is benzyl or, when R, is benzyl, is hydrogen or benzyl,

to produce a compound of Formula Ib,

wherein R is as defined above, or

wherein R is as defined above,

with a compound of Formula V,

R, is hydrogen, alkyl of 1 to 7- carbon atoms, or eycloalkyl orcycloalkylalkyl, in which the cycloalkyl ring is of 3 to 7 carbon atomsand the alkyl residue is of l to 5 carbon atoms, or phenylalkyl ordiphenylalkyl, in which the phenyl radicals may be substituted in the 3,4 or 5 position by 1 to 3 hydroxy or methoxy groups, or in the 3,4position by a methylenedioxy group, and are separated from the oxygenatom by at least two carbon atoms, and in which the alkyl residue is of1 to 5 carbon atoms, and

R is hydrogen or alkyl of 1 to 7 carbon atoms, or

R and R together with the carbon atom to which the oxygen atom is joinedform a cycloalkyl group of 4 to 7 carbon atoms, provided that when R isalkyl, when R, is alkyl the total number of carbon atoms in R and R isnot greater than 7, and when R, is cycloalkylalkyl, phenylalkyl ordiphenylalkyl the total number of carbon atoms in R and in the alkylresidue of R is not greater than 5,

under reductive alkylation conditions, to produce a compound of FormulaIc,

wherein R is cycloalkyl of 4 to 7 carbon atoms, primary or secondaryalkyl of l to 8 carbon atoms, cycloalkylalkyl, in which the cycloalkylring is of 3 to 7 carbon atoms and the alkyl residue is of 1 to 6 carbonatoms, or phenylalkyl or diphenylalkyl, in which the phenyl radicals maybe substituted in the 3, 4 or 5 position by 1 to 3 hydroxy or methoxygroups, or in the 3,4 position by a methylenedioxy group, and areseparated from the nitrogen atom by at least 2 carbon atoms, and inwhich the alkyl residue is of 2 to 6 carbon atoms, or

(d) Treating a compound of Formula VId,

R is as defined above, and each of R and R is alkyl of 1 to 4 carbonatoms,

with a metal hydride which will reduce an ester to an alcohol, andhydrolyzing the resulting reaction product, to produce a compound ofFormula I; and, if desired, separating any resulting racemates of thecompounds of Formula I into their optical antipodes and/or convertingthe resulting compounds of Formula I into their acid addition salts.

The alkyl groups represented by the symbols R may be straight-chained orbranched and preferably contain 1 to 4 carbon atoms; the cycloalkylgroups preferably contain ring members. The alkyl residue of the aralkylgroup may be straight-chained or branched and is preferably of 2 to 5carbon atoms.

Process variants (a) may be effected in accordance with conventionalmethods for ether splitting. Thus, for example, a compound of Formula IImay be allowed to react with a Lewis acid, e.g. boron tribromide oraluminium chloride, in an inert organic solvent, e.g. a halogenatedhydrocarbon such as methylenechloride or carbon tetrachloride, or anaromatic hydrocarbon such as toluene or benzene, at --80 to -+70 C., ora compound of Formula II may be treated for a short period with a strongmineral acid, e.g. hydrobromic or hydriodic acid, optionally at anelevated temperature, e.g. at approximately 20 to 100 C., or ahydrochloride, hydrobromide or hydriodide of an organic base such asaniline or pyridine is allowed to act on a compound of Formula II at anelevated temperature, e.g. about 20 to 100 C. In this process anymethoxy or methylenedioxy groups which are present in the substituent Rare also converted, so that a compound of Formula Ia is obtained.

The debenzylation in accordance with process variant (b) may, forexample, be effected by catalytic hydrogenation in an inert solvent,e.g. ethyl acetate, or a lower alkanol such as methanol or ethanol.Hydrogenation is preferably effected at a temperature from 20 to 100 C.,at a hydrogen pressure of 1 to 100 atmospheres. A palladium catalystmay, for example, be used as hydrogenation catalyst.

Process variant (c) may, for example, be efiected by catalytic reductionwith a platinum, palladium or nickel catalyst, at l to 100 atmosphereshydrogen pressure and at 20 to 80 C., in an inert solvent such asethanol.

In process variant (d) the metal hydrides suitable for the reaction are,for example, optionally complex aluminium metal hydrides, such aslithium aluminium hydried, aluminium hydride, diisobutyl aluminiumhydride, trialkoxy lithium aluminium hydrides, sodium dihydro-bis- (2methoxyethoxy)aluminate, or dibroane or lithium borohydride, and thereaction is preferably effected at room temperature. Reaction timesunder preferred conditions are from approximately /2 to several hours.

The compounds of Formula I may be isolated from the reaction mixture inconventional manner.

When optically active starting materials are used, the processes of theinvention yield optically active compounds of Formula I. When racemiccompounds are used as starting materials, the processes of the inventionyield racemates of the compounds of Formula I, which, if desired, may beseparated into the optical antipodes in conventional manner, e.g. byconverting the racemates with optically active acids into a mixture oftheir diastereoisomeric salts, and isolating the optical antipodes ofthe compounds of Formula I therefrom.

The compounds of Formula II may be obtained by a process comprising (on)Reducing the ester group in a compound of Formula VIa,

C 0 CR5 mo-Q-hn-cm-Nn-m wherein R R and R are as defined above, or 3)Reducing a compound of Formula VII,

wherein R and R are as defined above,

to produce a compound of Formula IIa,

wherein R is as defined above, or

('y) Reductively reacting a compound of Formula IIc,

wherein R is methyl or ethyl,

(IIa) wherein R and R are as defined above.

Process variants (oz) and 8) may, for example, be effected in an inertsolvent, e.g. an ether such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, with lithium aluminium hydride or aluminium hydride.

Process variants (a) and (7) yield optically active compounds of FormulaII when optically active compounds are used as starting materials. Whenracemic compounds are used as starting materials in both processes, aswell as in process variants (p), racemates of compounds of Formula IIare obtained, which may be separated into their optical antipodes inconventional manner, e.g. by converting racemates with optically activeacids into a mixture of their diastereoisomeric salts, and isolating theoptical antipodes of the compounds of Formula II therefrom.

wherein R is as defined above,

may, for example, be obtained by converting the ether groups intohydroxy groups in a compound of Formula 0 H: O H mocyms m wherein R andR are as defined above,

e.g. as described in process variant (a).

Compounds of Formula 111b,

onion omo A m-cuppa.

RI (IIIb) wherein R and R are as defined above,

may, for example, be obtained by reducing a compound ofFormula VIb,

C O 0 RI @0310 oH-om-I I-Rl" wherein R R, and R, are as defined above,

as described in process variant (3) Compounds of Formula VIII may, forexample, be obtained by reducing a compound of Formula VIc,

wherein R R and R are as defined above,

as described in process variant The compound of Formula IVa wherein Rand R are as defined above,

are a special case of the compounds of Formula IH.

Compounds of Formula VI,

COORs m0oH-orrr-N-R1 1i; wherein R R R and R are as defined above,

may, for example, be obtained by addition of a compound of Formula X,

NH-R

wherein R and R areas defined above,

to a compound of Formula IX,

wherein R and R are as defined above.

The reaction may, for example, be effected at 20 to C., using equimolaramounts of both compounds, and optionally in an inert solvent, e.g. alower alcohol.

Compounds of Formula VId may, for example, be obtained by reacting acompound of Formula IXa,

C O 0 Rs magma wherein R and R are as defined above, with a compound ofFormula Xa,

NHg-R wherein R is as defined above,

in accordance with the process described for the production of compoundsof Formula VI.

Insofar as the production of the starting materials is not particularlydescribed, these are known or may be produced in accordance with knownprocesses, or in a manner analogous to the processes described herein orto known processes.

The compounds of Formula I are useful because they possesspharmacological activity in animals. In particular, the compounds areuseful in the treatment of bronchospasms, such as in bronchial asthma,as indicated by their exhibition of generalized sympathomimetic,especially broncholytic, properties, as illustrated by their effect invagally induced bronchospasms, and bronchospasms produced by histamineand acetylcholine in cats and guinea pigs.

For the above-mentioned use, the dosage administered will, of course,vary depending on the compound employed, mode of administration andtreatment desired. However, in general satisfactory results are obtainedwhen administered at a daily dosage of from about 0.005 to 5 mg./kg.animal body weight, conveniently given in divided doses 2 to 3 times aday, or in sustained release form. For the larger mammals the totaldaily dosage is in the range of from about 10 to 20 mg., and dosageforms suitable for oral administration comprise from about 3 to 10 mg.of the compound admixed with a solid or liquid pharmaceutical carrier ordiluent.

3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol has particularlyinteresting properties.

The compounds of Formula I may be administered in pharmaceuticallyacceptable acid addition salt form. Such salts possess the same order ofactivity as the free bases and are readily prepared in conventionalmanner. Suitable such salt forms include organic acid salts such as thefumarate, maleate, tartrate, methane-, ethaneand benzenesulphonate,citrate and malate, and mineral acid 7 salts such as the hydrochloride,hydrobromide and sulphate.

The compounds of Formula I or their pharmaceutically acceptable acidaddition salts may be used as medicaments on their own or in the form ofappropriate medicinal preparations, e.g. tablets, drages, capsules,granules, suppositories or injectable solutions or suspensions, forenteral or parenteral administration. Aside from the usual inorganic ororganic pharmaceutically acceptable adjuvants, e.g. lactose, starch,talc, stearic acid, water, alcohols, natural or hardened oils and waxes,these preparations may also contain suitable preserving stabilizing orwetting agents, solubilizers, sweetening or coloring substances andflavorings.

The invention accordingly also provides a pharmaceutical compositioncomprising as active agent a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof, in association with apharmaceutical carrier or diluent.

In the following non-limitative examples all temperatures are indicatedin degrees centigrade and are uncorrected.

EXAMPLE 1 2-(3,4-dihydroxyphenyl(-3-(isopropylamino)propanol [processvariant (a)] 20 g. of 2-(3,4-dimethoxyphenyl)-3-isopropylaminopropanolare dissolved in 250 cc. of methylene chloride and cooled to 75". 45 g.of boron tribromide in the form of a 1 molar solution in methylenechloride are slowly added dropwise while stirring at such a rate thatthe temperature does not exceed 70. After 5 hours the solvent isdistilled off in a vacuum, the residue is heated under reflux for 1 hourwith 100 cc. of ethanol, the reaction solution is concentrated byevaporation and the residue is recrystallized from ethanol/ether. Thebydrobromide of the title compound has a M.P. of 87-91".

The 2 (3,4-dimethoxyphenyD-3-(isopropylamino)propanol, required asstarting material, may be produced as follows:

(a) A solution of 472 g. of 3,4-dimethoxyatropic acid ethyl ester in 200cc. of ethanol is added dropwise to a solution of 140 g. ofisopropylamine in 200 cc. of ethanol at room temperature while stirring.The reaction solution is subsequently heated to 50 for 3 hours, isfiltered and the filtrate is concentrated by evaporation in a vacuum.The residue is taken up in chloroform and extracted with 2 Nhydrochloric acid. The hydrochloric acid solution is rendered alkalinewith concentrated ammonia while cooling, whereby crude2-(3,4-dimethoxyphenyl)-3-(isopropylamino)propionic acid ethyl esterseparates as a yellow oil, and this is taken up in chloroform. Thesolution is dried over sodium sulphate and concentrated by evaporation;the residue is converted into the hydrochloride with hydrochloric acidin ethanol. M.P. 159-162".

(b) 96 g. of 2-(3-di'methoxyphenyl)-3-(isopropylamino)propionic acidethyl ethyl ester are reduced in 1000 cc. of ether with 11.4 g. oflithium aluminium hydride by heating under reflux for two hours. Afterdecomposing with a small amount of water, filtration is effected, theether solution is dried and concentrated by evaporation, and2-(3,4-dimethoxyphenyl) 3 (isopropylamino)propanol is crystallized. M.P.59-61; the hydrochloride has a M.P. of 150-152.

EXAMPLE 2 3-tert.-butylamino-2-(3,4-dihydroxyphenyl) propanol3-tert.-butylamino-2-(3,4 di-methoxyphenyl)-propanol (obtained in amanner analogous to Example 1, M.P. 71- 73) is reacted in accordancewith the process described in Example 1. The hydrobromide of the titlecompound has a M.P. of 113-115".

8 EXAMPLE 3 3-sec.butylamino-2-( 3,4-dihydroxyphenyl) propanol3-sec.butyla'mino-2-(3,4-dimethoxyphenyl)propanol obtained in a manneranalogous to Example 1, oil) is reacted in accordance with the processdescribed in Example 1. The hydrobromide of the title compound has aM.P. of -89".

EXAMPLE 4 3-butylamino-2- 3,4-dihydroxyphenyl)propanol3-butylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manneranalogous to Example 1, M.P. 70- 72) is reacted in accordance with theprocess described in Example 1. The hydrobromide of the title compoundhas a M.P. of 93-9'5.

EXAMPLE 5 '3-cyclohexylarnino-2-(3,4-dihydroxyphenyl)propanol3-cyclohexylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manneranalogous to Example 1, oil) is reacted in accordance with the processdescribed in Example 1. The hydrobromide of the title compound has aM.P. of 95-97".

EXAMPLE 6 3-cyclopentylamino-2- 3,4-dihydroxyphenyl propanol3-cyclopentylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manneranalogous to Example 1, M.P. of the bis-naphthalene 1,5-disulphonate231-235) is reacted in accordance with the process described in Examplel. The hydrobromide of the title compound has a M.P. of 92-95 EXAMPLE 73-cyclopropylamino-2- (3,4-dihydroxyphenyl) propanol3-cyclopropylamino-2-(3,4 dimethoxyphenyDpropanol (obtained in a manneranalogous to Example 1, M.P. of the hydrochloride 132-134") is reactedin accordance with the process described in Example 1. The hydrobromideof the title compound has a M.P. of 56-60".

EXAMPLE 8 2-(3,4-dihydroxyphenyl) -3-(3-phenylpropylamino propanol2-(3,4-dimethoxyphenyl) 3 (3-phenylpropylamino) propanol (obtained in amanner analogous to Example 1, M.P. of the hydrochloride Ill-114) isreacted in accordance with the process described in Example 1. Thehydrobromide of the title compound has a M.P. of 108-110".

EXAMPLE 9 2-( 3,4-dihydroxyphenyl -3- l-phenyl- 2-propylamino propanol2-(3,4-dimethoxyphenyl)-3-(l-phenyl 2 propylamino) propanol (obtained ina manner analogous to Example 1, M.P. of thebis-naphthalene-1,5-disulphonate 76-80, decomp.) is reacted inaccordance with the process described in Example 1. The hydrobromide ofthe title compound has a M.P. of 109-1l0.

EXAMPLE 10 9 EXAMPLE 11 20 g. of 3-amino 2 (3,4 dimethoxyphenyl)propanolare dissolved in 250 cc. of methylene chloride and 52.5 g. of borontribromide in the form of a 1 molar solution in methylene chloride areslowly added at --75 while stirring. After hours the solvent isdistilled off in a vacuum, the residue is heated under reflux with 100cc. of ethanol for 1 hour, the reaction solution is concentrated byevaporation and the residue is recrystallized from ethanol/ ether. Thehydrobromide of the title compound has a M.P. of 87-91".

The 3-amino 2 (3,4-dimethoxyphenyl)propanol, required as startingmaterial, may be obtained as follows:

13 g. of concentrated sulphuric acid are added dropwise to a suspensionof 10.7 g. of lithium aluminium hydride in 500 cc. of tetrahydrofuranwhile stirring and cooling with ice. The mixture is stirred for afurther 15 minutes and a solution of 25 -g. of3,4-dimethoxy-phenylcyanoacetic acid ethyl ester in 50 cc. oftetrahydrofuran is added dropwise at 20. The reaction mixture issubsequently stirred at 50 for a further 3 hours, the residual lithiumaluminum hydride is then destroyed with a caustic soda solution,filtration is effected, the tetrahydrofuran solution is dried overpotassium carbonate and the solvent is distilled ofi. The resulting oilis converted into the hydrochloride and recrystallized fromethanol/ether. The hydrochloride has a M.P. of 204-206.

EXAMPLE 12 2-(3,4-dihydroxyphenyl)-3-(n-propylamino)propanol 2-(3,4dimethoxyphenyl) 3 (n-propylamino)propanol (obtained in a manneranalogous to Example 1, M.P. 72-74") is reacted in accordance with theprocess described in Example 1. The hydrobromide of the title compoundhas a M.P. of 84-85 EXAMPLE 13 2-(3,4-dihydroxyphenyl)-3-(4-methyl-2-pentylamino propanol 2-(3,4 dimethoxyphenyl) 3 (4-methyl-2-pentylamino)propanol (obtained in a manner analogous to Example l, M.P. of thehydrochloride 125127) is reacted in accordance with the processdescribed in Example 1. The hydrobromide of the title compound has aM.P. of 145-147.

EXAMPLE 14 2-(3,4-dihydroxyphenyl)-3- (phenethylamino)propanol 2-(3,4dimethoxyphenyl) 3 (phenethylamino)propanol (obtained in a manneranalogous to Example 1, M.P. of the hydrochloride 149-151) is reacted inaccordance with the process described in Example 1. The bydrobromide ofthe title compound has a M.P. of 65-70.

EXAMPLE 15 2- 3,4-dihydroxyphenyl) -3- (n-pentylamino) propanol 2-(3,4dimethoxyphenyl) 3 n-pentylamino)propanol (obtained in a manneranalogous to Example 1, M.P. of the hydrochloride 133-136) is reacted inaccordance with the process described in Example 1. The hydrobromide ofthe title compound has a M.P. of 139141.

EXAMPLE 16 3- (n-hexylamino) -2- (3,4-dihydroxyphenyl propanol3-(n-hexylamino) 2 (3,4-dimethoxyphenyl)propanol (obtained in a manneranalogous to Example 1, M.P. of the hydrochloride 94-97") is reacted inaccordance with the process described in Example 1. The hydrobromide ofthe title compound has a M.P. of 92-95.

10 EXAMPLE 11 3-(n-heptylamino)-2-(3,4-dihydroxyphenyl)propanolS-(n-heptylamino) 2 (3,4-dimethoxyphenyl)propa- 1101 (obtained in amanner analogous to Example 1, oil) is reacted in accordance with theprocess described in Example 1. The hydrobromide of the title compoundhas a M.P. of 128-13l.

EXAMPLE l8 2-(3,4-dihydroxyphenyl)-3-(4-phenylbutylamino)propanol2-(3,4-dimethoxyphenyl) 3 (4 phenylbutylamino) propanol (obtained in amanner analogous to Example 1, M.P. of the hydrochloride 116-118) isreacted in accordance with the process described in Example 1. Thehydrobromide of the title compound has a M.P. of 117 EXAMPLE 193-(p-hydroxyphenethylamino)-2-(3,4-dihydroxyphenyl)propanol3-(p-methoxyphenethylamino) 2 (3,4 dimethoxyphenyl)propanol (obtained ina manner analogous to Example l, M.P. of the hydrochloride 144-146) isreacted in accordance with the process described in Example 1. Thehydrobromide of the title compound has a M.P. of 6570.

EXAMPLE 20 2-(3,4-dihydroxypheny1)-3-[3-(p-hydroxyphenyl)propylarnino]propanol 2-(3,4-dimethoxyphenyl)-3 [3 (p methoxyphenyl)propylamino]propanol (obtained in a manner analogous to Example 1, M.P.6467, M.P. of the hydrochloride 104-106") is reacted in accordance withthe process described in Example 1. The hydrobromide of the titlecompound has a M.P. of -168".

EXAMPLE 21 2-(3,4-dihydroxyphenyl) -3- 1-phenyl-3-butylamino) propanol2-(3,4-dimethoxyphenyl)-3-( l-phenyl 3 butylamino) propanol (obtained ina manner analogous to Example 1, M.P. of the hydrochloride 118120) isreacted in accordance with the process described in Example 1. Thehydrobromide of the title compound has a M.P. of 90-94".

EXAMPLE 22 3-ethylamino-2-(3,4-dihydroxyphenyl)propanol3'ethylamino-2-(3,4 dimethoxyphenyl)propanol (obtained in a manneranalogous to Example 1, M.P. 67- 69") is reacted in accordance with theprocess described in Example 1. The hydrobromide of the title compoundhas a M.P. of 93-95 EXAMPLE 233-(4-hydroxybenzylamino)-2-(3,4-dihydroxyphenyl) propanol3-(3,4-dihydroxyphenethylamino)-2-(3,4-dihydroxyphenyl)propanol3-(3,4-dimethoxyphenethylamino)-2-(3,4 dimethoxyphenyl)propanol(obtained in a manner analogous to Example 1, M.P. of the hydrogenfumarate (SS-67) is reacted in accordance with the process described inExample 11 1. The hydrobromide of the title compound has a M.P. of77-80".

EXAMPLE 25 2-(3,4-dihydroxyphenyl)-3-(2,2-diphenylethylamino) propanol(+)-3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol hydrobromide(+)-3-tert.butylamino 2 (3,4 dimethoxyphenyl) propanol is reacted inaccordance with the process described in Example 1. The title compoundhas a M.P. of

102-104, [a] =+31.5 in ethanol.

EXAMPLE 27 -3 -tert.butylamino-2- (3 ,4-dihydroxyphenyl propanolhydrobromide ()-3-tert.butylamino 2 (3,4 dimethoxyphenyl) propanol isreacted in accordance with the process described in Example 1. The titlecompound has a M.P. of 107-109, [a] =32.1 in ethanol.

The starting materials for Examples 26 and 27, i.e.

(+)- or ()-3-tert.butyl-amino 2 (3,4 dimethoxyphenyl)propanol, areobtained as follows:

(a) A solution of 472 g. of 3,4-dimethoxyatropic acid ethyl ester in 200cc. of ethanol is added dropwise to a solution of 175 g. oftert.butylamine in 200 cc. of ethanol at room temperature whilestirring. The reaction mixture is subsequently heated to 50 for 3 hours,filtration is etfected and the filtrate is concentrated by evaporationin a vacuum. The residue is taken up in chloroform and extracted with 2N hydrochloric acid. The hydrochloric acid solution is rendered alkalinewith concentrated ammonia while cooling, whereby a yellow oil separates,which is taken up in chloroform. The solution is dried over sodiumsulphate and concentrated by evaporation. The residue, i.e.3-tert.butylamino-2-(3,4 dimethoxyphenyl)propionic acid ethyl ester, isconverted into the hydrochloride with hydrochloric acid in ethanol.

(b) 105 g. of 3-tert.butylamino-2 (3,4 dimethoxyphenyl)propionic acidethyl ester are reduced in 1000 cc. of ether with 11.4 g. of lithiumaluminium hydride by heating under reflux for two hours. Afterdecomposing with a small amount of water, filtration is effected, theether solution is dried and concentrated by evaporation, and theresidue, the racemate form of 3-tert.butylarnino-2- (3,4dimethoxyphenyl)propanol, is crystallized. The racemate has a M.P. of71-73 -(c) 40 g. of racemic3-tert.butylamino-2-(3,4-dimethoxyphenyl)propanol are dissolved in 4liters of ethanol and a solution of 60 g. of ()di-O (p toluoyl) L-tartaric acid in 4 liters of ethanol is added. (+)-3-tert.butylamino-Z-(3,4-dimethoxyphenyl) propanol hydrogen-(-)di-O-(p-toluoyl)-L-tartrate crystallizes. M.P. afterrecrystallization from methanol l91-192.

The salt of the optically active base is decomposed with 2 N causticsoda solution/ chloroform; the base resulting from the chloroform phaseis recrystallized from cyclohexane. (+)-3-tert.butylamino-2-(3,4-dimethoxyphenyl) propanol is obtained. M.P. 707l, [a]=I-31.90 in ethanol.

((1) The ethanolic mother liquor obtained in (c) above is concentratedby evaporation, the resulting salt mixture is decomposed with 2 Ncaustic soda solution, the liberated base is taken up in chloroform, thesolution is dried over sodium sulphate, the chloroform is distilled 011and the resulting base is dissolved in 2.5 liters of ethanol. A solutionof 40 g. of (+)-di-O-(p-toluoyl)-D-tartaric acid in 2.5 liters ofethanol is added to this solution. ()-3-tert. butylamino-2-(3,4dimethoxyphenyl)propanol hydrogen- (+)-di-O-(p-toluoyl)-D-tartratecrystallizes. M.P. after recrystallization from methanol 191-192".

The salt of the optically active base is decomposed with 2 N causticsoda solution/ chloroform. The base resulting from the chloroform phaseis recrystallized from cyclohexane. )-3-tert.butylamino-2-( 3,4dimethoxyphenyl)propanol is obtained. M.P. 77-79 [a] =32.5 in ethanol.

EXAMPLE 28 3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol 10.0 g. ofracemic 3-tert.butylamino 2-(3,4-dimethoxyphenyl)propanol (prepared asdescribed in Example 27) are heated under refiux in 100 cc. of 48%hydrobromic acid for 15 minutes. The reaction solution is subsequentlyevaporated to dryness and the residue is recrystallized fromethanol/ether.

The hydrobromide of the title compound has a M.P. of 113-1 15.

EXAMPLE 29 2(3,4-dihydroxyphenyl)-3-(p-methoxyphenethylamino) propanol[process variant (b)] 11.0 g. of 2-(3,4-dibenzyloxyphenyl) 3(p-methoxyphenethylamino)propanol are dissolved in 200 cc. of ethanol,1.0 g. of palladium on charcoal (10%) is added and hydrogenation isefiected at room temperature for 30 minutes. The catalyst is thenfiltered 01f, the solution is concentrated by evaporation and theresidue is converted into the hydrochloride of the title compound. M.P.198-200.

The starting material is obtained as follows:

(a) 7.6 g. of sodium are dissolved in 200 cc. of ethanol, the solutionis evaporated to dryness in the absence of moisture and the residue issuspended in 200 cc. of absolute toluene. 80 g. of oxalic acid diethylester are added dropwise and subsequently 123 g. of3,4-dibenzyloxyphenylacetic acid ethyl ester are added dropwise at 35-40 while stirring. The mixture is heated under reflux while stirring for2 hours, is then cooled to 45 and cc. of 4 N sulphuric acid are added.40 g. of 36% formalin and cc. of a saturated potassium carbonatesolution are added over a period of 3 hours. The reaction mixture isstirred at room temperature over night, is then diluted with 250 cc. ofwater and the toluene phase is separated. After drying over sodiumsulphate the solvent is distilled off, and the resultinga-(3,4-dibenzyloxyphenyl)acrylic acid ethyl ester is used for the nextreaction without previous purification.

(b) 38.8 g. of u-(3,4-dibenzyloxyphenyl)acrylic acid ethyl ester and 14g. of p-methoxyphenethylamine are heated under reflux in cc. of ethanolfor 10 hours. After distilling off the ethanol, the residue is dissolvedin 300 cc. of ether and the solution is shaken with 25 cc. of 4 Nhydrochloric acid, whereby the hydrochloride of2-(3,4-dibenzyloxyphenyl) 3 p methoxy-phenethylaminopropionic acid ethylester crystallizes. M.P. 85-88 after recrystallization fromethanol/ether.

(c) 16.7 g. of2-(3,4-dibenzyloxyphenyl)-3-p-methoxyphenethylaminopropionic acid ethylester are reduced in 200 cc. of tetrahydrofuran with 2.0 g. of lithiumaluminium hydride. The reaction is complete after heating under refluxfor 2 hours. After decomposing the excess reducing agent with a smallamount of water, filtration is effected and the tetrahydrofuran solutionis dried over sodium sulphate and the solvent is distillated ofi. Theresulting 2-(3,4-dibenzyloxyphenyl)-3-(p methoxyphenethylamino)propanolis recrystallized from ethyl acetate/ petroleum ether. M.P. 81-82".

13 EXAMPLE 3o 2- 3,4-dihydroxyphenyl) -3- (isopropylamino propanol[process variant 3-n-butylamino-2- (3 ,4-dihydroxyphenyl) propanol 5.0of 3 amino-2-(3,4 dihydroxyphenyl)propanol hydrobromide are reacted withbutyraldehyde in analogous manner to Example 30. The hydrobromide of thetitle compound has a M.P. of 93-95 EXAMPLE 32 3 -sec.butylamino-2- (3,4-dihydroxyphenyl) propanol 3-amino-2-(3,4 dihydroxyphenyl)propanol isreacted with methyl ethyl ketone in accordance with the processdescribed in Example 30. The hydrobromide of the title compound has aM.P. of 85-89".

EXAMPLE 33 3-cyclohexylamino-2-(3,4-dihydroxyphenyl)propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with cyclohexanone inaccordance with the process described in Example 30. The hydrobromide ofthe title compound has a M.P. of 95-97".

EXAMPLE 34 3-cyclopentylamino-2-(3,4-dihydroxyphenyl)propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with cyclopentanonein accordance with the process described in Example 30. The hydrobromideof the title compound has a M.P. of 92-95.

EXAMPLE 35 2-(3,4-dihydroxyphenyl)-3-(3-phenylpropylamino) propanol3-amino-2-(3,4dihydroxypheny1)propanol is reacted with3-phenylpropionaldehyde in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of108-110".

EXAMPLE 36 2- (3 ,4-dihydroxyphenyl) -3 1-phenyl-2-propylamino) propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with benzyl methylketone in accordance with the process described in Example 30. Thehydrobromide of the title compound has a M.P. of 109-110".

EXAMPLE 37 2-(3,4-dihydroxyphenyl)-3-(3,3-diphenylpropylamino) propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with3,3-diphenylpropionaldehyde in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of 98402".

EXAMPLE 38 2- (3,4-dihydroxyphenyl)-3-(n-propylamino) propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with propionaldehydein accordance with the process described in Example 30. The hydrobromideof the title compound has a M.P. of 84-85.

14 EXAMPLE 39 2-(3,4-dihydroxyphenyl)-3-(4methyl-2-pentylamino) propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with4-methyl-2-pentanone in accordance with the process described in Example30. The hydrobromide of the title compound has a M.P. of l45-147.

EXAMPLE 4O 2- 3,4-dihydroxyphenyl) -3- (phenethylamino propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted withphenylacetaldehyde in accordance with the process described in Example30. The hydrobromide of the title compound has a M.P. of 65-70.

EXAMPLE 41 2-(3,4-dihydroxyphenyl)-3-(n-pentylamino)propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with valeraldehyde inaccordance with the process described in Example 30. The hydrobromide ofthe title compound has a M.P. of 139-141.

EXAMPLE 42 3- n-hexylamino -2- 3 ,4-dihydroxyphenyl propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with hexanal inaccordance with the process described in Example 30. The hydrobromide ofthe title compound has a M.P. of 92-95 EXAMPLE 43 3-(n-heptylamino -2-(3,4-dihydroxyphenyl) propanol 3-amino-2-(3,4-dihydroxyphenyl)propanolis reacted with n-heptanal in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of128-13l.

EXAMPLE 44 2- (3,4-dihydroxyphenyl) -3 (4-phenylbutylamino) propanol3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted with4-phenylbutyraldehyde in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of115-117".

EXAMPLE 45 3- (p-hydroxyphenethylamino -2- 3 ,4-dihydroxypheny1)propanol 3-amino-2-(3,4-dihydroxyphenyl)propanol is reacted withp-hydroxy-phenylacetaldehyde in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of 65-70".

EXAMPLE 46 2.- 3,4-dihydroxyphen'yl) -3- 3- (p-hydroxyphenyl)propylamino1propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reactedwith 3-(p-hydroxyphenyl)propionaldehyde in accordance with the processdescribed in Example 30. The hydrobromide of the title compound has aM.P. of l65-16=8.

EXAMPLE 47 2-(3,4-dihydroxyphenyD-3-(l-phenyl-3-butylamino) propanol3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with4-phenyl-2-butanone in accordance with the process described in Example30. The hydrobromide of the title compound has a M.P. of -9'4.

1 EXAMPLE 48 3-ethylamino-2-(3,4-dihydroxyphenyl)propanol 3-amino 2(3,4-dihydroxyphenyl)propanol is reacted with acetaldehyde in accordancewith the process described in Example 30. The hydrobromide of the titlecompound has a M.P. of 93-95".

EXAMPLE 49 3-(3,4-dihydroxyphenethylamino)-2-(3,4-dihydroxyphenylpropanol S-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with3,4-dihydroxy-phenylacetaldehyde in accordance with the processdescribed in Example 30. The hydrobromide of the title compound has aM.P. of 77-80.

EXAMPLE 50 2-(3,4-dihydroxyphenyl)-3-(2,2-diphenylethylamino) propanol3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted withdiphenylacetaldehyde in accordance with the process described in Example30. The hydrobromide of the title compound has a M.P. of (HS-117.

EXAMPLE 51 2-(3,4 dihydroxyphenyl)-3-(p-methoxyphenethylamino) propanol3-amino 2 (BIA-dihydroxyphenyl)propanol is reacted withp-methoxy-phenylacetaldehyde in accordance with the process described inExample 30. The hydrochloride of the title compound has a M.P. of198-200.

EXAMPLE 5 2 3-[ (cyclopentylmethyl) amino] -2-( 3,4-dihydrox'yphenyl)propanol [process variant (a)] 20.0 g. of3-[(cyclopentylmethyl)amino]-2-(3,4-dimethoxyphenyDpropanol aredissolved in 250 cc. of methylene chloride and 39 g. of borontribromide, dissolved in 250 cc. of methylene chloride, are addeddropwise thereto while maintaining the reaction temperature at -75. Thecooler is then removed, the reaction mixture is stirred at roomtemperature for 1 hour and the solvent is then distilled 01f. Theresidue is boiled under reflux with 100 cc. of ethanol for 1 hour. Thesolution is concentrated and ether is added until the reaction productcrystallizes as hydrobromide. M.P. 87-91 (decomp.).

The starting material is obtained as follows:

(a) 52.0 g. of 3,4-dimethoxyatropic acid ethyl ester and 19.8 g. ofcyclopentylmethylamine are heated to 60 with 20 cc. of ethanol for 3hours. The reaction mixture is concentrated by evaporation in a vacuum,the oily residue is dissolved in chloroform and extraction is effectedwith 2 N hydrochloric acid. The hydrochloric acid solution is renderedalkaline with concentrated ammonia while cooling and is then extractedwith chloroform. The chloroform extract is dried over sodium sulphateand concentrated by evaporation and the residue, i.e.3-[(cyclopentylmethyl amino] -2- (3,4 dimethoxyphenyl) propionic acidethyl ester, is converted into the hydrochloride with hydrochloric acidin ethanol. M.P. 127-129.

(b) 50 g. of3-[(cyclopentylmethyl)amino]-2-(3,4-dimethoxyphenyl)propionic acid ethylester are reduced in 400 cc. of tetrahydrofuran with 6.5 g. of lithiumaluminium hydride by heating for 2 hours. After decomposing the residualreducing agent with a small amount of water, filtration, drying andconcentrating by evaporation are effected and3-[(cyclopentylmethyl)amino]-2-(3,4-dimethoxyphenyl)propanol iscrystallized from ethyl acetate/petroleum ether. M.P. 67-70.

16 EXAMPLE s3 3,(3-cyclopentylpropylamino)-2-(3,4-dihydroxyphenyl)propanol EXAMPLE 54 3-[ (cyclohexylmethyl) amino] -2-3,4-dihydroxyphenyl) propanol 3-[ (cyclohexylmethyl) amino]-2-(3,4dimethoxyphenyl)propanol is reacted in accordance with the processdescribed in Example 1. The hydrobromide of the title compound has aM.P. of 112-115".

The starting materials are produced in a manner analogous to thatdescribed in Example 52:

(a) Reaction of 3,4-dimethoxyatropic acid ethyl ester withcyclohexylmethylamine yields 3 [(cyclohexylmethyl)amino] 2 (3,4dimethoxyphenyl)propionic acid ethyl ester, M.P. of the hydrochloride-133, and

(b) Reduction of the latter yields I i-[(cyclohexylmethy1)amino] 2 (3,4dimethoxyphenyl)propanol, M.P. 130-132.

EXAMPLE 55 3- (cyclopentylmethyl)amino] -2-(3,4- dihydroxyphenylpropanol 3 amino 2-(3,4-dihydroxyphenyl)propanol is reacted withcyclopentylformaldehyde in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of 87-91(decomp.).

EXAMPLE 5 6 3- 3-cyclopentylpropylamino) -2- 3,4-dihydroxyphenyl)propanol 3-amino 2 (3,4-dihydroxyphenyl)propanol is reacted with 3cyclopentylpropanone in accordance with the process described in Example30. The hydrobromide of the title compound has a M.P. of 164-167.

EXAMPLE 5 7 3- (cyclohexylmethyl) amino] -2-( 3,4-dihydroxyphenylpropanol 3 amino 2 (3,4-dihydroxyphenyl)propanol is reacted withcyclohexylfor-maldehyde in accordance with the process described inExample 30. The hydrobromide of the title compound has a M.P. of 112-115What is claimed is:

1. A compound of the formula:

R is alkyl of l to 8 carbon atoms, or a pharmaceutically acceptable acidaddition salt thereof.

2. The compound of claim 1, which is 2-(3,4-dihydroxyphenyl) 3(isopropylamino)propanol.

3. The compound of claim 1, which is 3-tert.butylamino-2-(3,4-dihydroxyphenyl)propanol.

1 7 4. The compound of claim 1, which is 3-sec. butylamino-2-(3,4-dihydroxyphenyl prop anol.

5. The compound of claim 1, which is 3-butylamino-2-(3,4-dihydroxyphenyl)propanol.

6. The compound of claim 1, which is 2-(3,4-dihy- 5 droxyphenyl) -3-n-propylamino propanol.

7. The compound of claim 1, which is2-(3,4-dihydroxyphenyl)-3-(4-methyl-2-pentylamino)propanol.

8. The compound of claim 1, which is2-(3,4-dihydroxyphenyl)-3-(n-pentylamino)propanol.

9. The compound of claim 1, which is 3-(n-hexylamino) -2-3,4-dihydroxyphenyl) propanol.

10. The compound of claim 1, which isS-(n-hcptylamino)-2-(3,4-dihydroxypheny1)propanol.

18 12. The compound of claim 1, which is 3-tert.- butylamino2-(3,4-dihydroxyphenyl)proanol hydrobromide.

13. The compound of claim 1, which is 3 tertbutylamino 2(3,4-dihydroxyphenyl)propanol hydrobromide.

References Cited Meschino et al.: Journal of Organic Chemistry, vol. 28,No. 11, pp. 3129-3134 (1963).

ROBERT V. HINES, Primary Examiner US. Cl. X.R.

11. The compound of claim 1, which is 3-ethy1amino- 5 260-4405, 465 DF,471 A, 473 S, 501.17, 501.18, 501.19,

2-(3,4-dihydroxyphenyl)propanol.

